Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology

Masayuki Ide, Tetsuo Ohnishi, Manabu Toyoshima, Shabeesh Balan, Motoko Maekawa, Chie Shimamoto-Mitsuyama, Yoshimi Iwayama, Hisako Ohba, Akiko Watanabe, Takashi Ishii, Norihiro Shibuya, Yuka Kimura, Yasuko Hisano, Yui Murata, Tomonori Hara, Momo Morikawa, Kenji Hashimoto, Yayoi Nozaki, Tomoko Toyota, Yuina WadaYosuke Tanaka, Tadafumi Kato, Akinori Nishi, Shigeyoshi Fujisawa, Hideyuki Okano, Masanari Itokawa, Nobutaka Hirokawa, Yasuto Kunii, Akiyoshi Kakita, Hirooki Yabe, Kazuya Iwamoto, Kohji Meno, Takuya Katagiri, Brian Dean, Kazuhiko Uchida, Hideo Kimura, Takeo Yoshikawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2S)/polysulfide-producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst-deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst-transgenic (Tg) mice showed deteriorated PPI, suggesting that “sulfide stress” may be linked to PPI impairment. Analysis of human samples demonstrated that the H2S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst-Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2S/polysulfides production.

Original languageEnglish
Article numbere10695
JournalEMBO Molecular Medicine
Volume11
Issue number12
DOIs
Publication statusPublished - 2019 Dec 1

    Fingerprint

Keywords

  • energy metabolism
  • epigenetics
  • hydrogen sulfide and polysulfides
  • prepulse inhibition
  • proteomics

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Ide, M., Ohnishi, T., Toyoshima, M., Balan, S., Maekawa, M., Shimamoto-Mitsuyama, C., Iwayama, Y., Ohba, H., Watanabe, A., Ishii, T., Shibuya, N., Kimura, Y., Hisano, Y., Murata, Y., Hara, T., Morikawa, M., Hashimoto, K., Nozaki, Y., Toyota, T., ... Yoshikawa, T. (2019). Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology. EMBO Molecular Medicine, 11(12), [e10695]. https://doi.org/10.15252/emmm.201910695